Clinical outcomes of immunomodulation therapy in immunocompromised patients with severe Covid-19 and high oxygen requirement.

Covid-19 disease is implicated in increased mortality among immunocompromised patients. The JAK inhibitor, baricitinib (bar), or the IL-6 inhibitor, tocilizumab (toc), demonstrated a survival benefit in patients with severe disease.However, evidence supporting their use in immunocompromised patients with severe Covid-19 is scarce.We aimed to assess clinical outcomes of bar/toc treatment in immunocompromised patients. A multi-center registry of consecutive immunocompromised patients hospitalized due to severe Covid-19 during the Omicron variant dominance period. After excluding patients who did not require high oxygen supply, patients treated with bar/toc were compared to patients treated by standard of care (SOC). Primary outcome was in hospital mortality. Secondary outcomes were 30 and 60 day mortality, super-infection and thromboembolic events. Among an overall 228 immunocompromised patients hospitalized in six Israeli hospitals with severe Covid-19, 112 patients required high oxygen support, of whom 48 (43%) were treated with bar/toc. In-hospital mortality rates were exceptionally high and did not significantly differ between bar/toc and SOC treated patients (62.5% vs. 64.1%, p = 1.0). A logistic regression analysis revealed that advanced age and incomplete vaccination were predictors of in-hospital mortality. Patients treated with bar/toc had no excess of suspected super-infection (62.8% vs. 60.7%, p = 0.84) or thromboembolic events (8.3% vs 3.1%, p = 0.39). In immunocompromised patients with severe Covid-19 and a high oxygen demand, bar/toc therapy was not associated with reduced mortality or with a higher rate of associated complications, compared to SOC. Larger prospective studies should better address efficacy and safety.

In vivo selection of carbapenem resistance during persistent Klebsiella pneumoniae sequence type 395 bloodstream infection due to OmpK36 deletion.

Non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP CRE) may be associated with a grave outcome. The common underlying mechanism is beta-lactamases and mutations in outer membrane porins. We report a case of a deep-seated infection caused by Klebsiella pneumoniae ST395 not amenable to source control, involving recurrent bloodstream infection, resulting in in vivo selection of carbapenem resistance under therapy. Three consecutive K. pneumoniae blood isolates were studied using short- and long-read sequencing. The genomes were subject to resistome and virulome, phylogenetic, and plasmid analyses. ompK36 porins were analyzed at the nucleotide and amino acid levels. Genomes were compared to 297 public ST395 K. pneumoniae genomes using cgMLST, resistome, and porin analyses and the EuSCAPE project. Relevant ompK36 and micF sequences were extracted and analyzed as above. The three sequential K. pneumoniae blood isolates belonged to the same clone. Subsequent CR isolates revealed a new large deletion of the ompK36 gene also involving the upstream region (deletion of micF). Comparison with public ST395 genomes revealed the study isolates belonged to clade B, representing a separate clone. N-terminal large ompK36 truncations were uncommon in both public data sets. In vivo selection of non-CP CRE K. pneumoniae could have substantial clinical implications. Such selection should be scrutinized through repeated cultures and frequent susceptibility testing during antimicrobial treatment, especially in the context of persistent or recurrent bloodstream infections and when adequate source control cannot be achieved. The occurrence of an unusually large deletion involving the ompK36 locus and upstream micF should be further studied.

Invasive infections caused by the recently described species Enterococcus innesii.

E. innesii is a recently described Enterococcus species which may be difficult to differentiate from the more common E. casseliflavus. We present the first clinical report of invasive E. innesii infection, featuring two cases of biliary sepsis. Whole genome sequencing confirmed the taxonomic assignment and the presence of vanC-4. Analysis of public genomes identified 13 deposited E. innesii and 13 deposited E. casselifalvus/E.gallinarum genomes which could be reassigned as E. innesii. Improved laboratory diagnosis of E. innesii is expected to generate additional data concerning its clinical relevance and support the future diagnosis and treatment of this uncommon pathogen.

Diagnosis and Risk Factors of Prediabetes and Diabetes in People Living With Human Immunodeficiency Virus: Evaluation of Clinical and Microbiome Parameters.

Diabetes mellitus (DM) is more common among people living with human immunodeficiency virus (PLWH) compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%), and diabetic (6.9%) PLWH. Glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher body mass index, Ethiopian origin, HIV duration, lower integrase inhibitor exposure, and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1c likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation.

Timing of midstream urine culture before endourological procedure-can we do better?-A comparative study.

Endourological procedures are the mainstay of treatment for stone disease in the upper urinary system. Infection is a common complication, and urine cultures (UC) are often obtained preoperatively. In this study, we sought to investigate the role of positive UC in the 90 days prior to surgery (90PreOp) in predicting postoperative infectious complications in comparison to a single positive preoperative UC (PreOP). We compared the correlation between positive PreOp UCs and positive 90PreOp UCs with postoperative urosepsis, and a positive UC obtain proximal to obstruction (Prox UC) during percutaneous nephrolithotomy, ureteroscopy and a placement of nephrostomy tube or ureteral stent. Data from 140 consecutive patients were collected. PreOp UCs were positive in 15 (11%) of patients versus 31 of 140 (22%) positive 90PreOp UCs. All six sepsis events had a positive 90PreOp UC, and five had a positive PreOp UC. Fourteen (93.3%) out of 15 positive Prox UC had a positive 90PreOp UC, whereas only 7 (38.9%) had a positive 90PreOp UC. Positive 90PreOp UC outperformed PreOp UC in predicting positive Prox UC, OR = 12.8 (95% CI 3.70-44.30, p < 0.001), versus OR of 88.9 (95% CI 11.0-720.7, p < 0.001); sensitivity 93%(95% CI 68-100%) versus 47%(95% CI 21-73%); as well as area under the ROC curve(AUC), 0.90 (CI 0.80-0.95) for 90PreOp versus 0.70 (CI 0.56-0.82) for positive Prox UC. Uropathogen persistence was better identified when using 90PreOp UC (27%) than using PreOp UC (12%). We suggest reviewing UCs taken within 90 days preoperatively as this was found superior to a single preoperative midstream UCs in predicting postoperative infectious sequela after stone procedure.

High rate of adenovirus detection in gastrointestinal biopsies of symptomatic stem cell transplant recipients.

OBJECTIVES: The gastrointestinal (GI) tract is a major human adenovirus (HAdV) replication site in patients undergoing hematopoietic stem cell transplantation (HSCT), yet the prevalence and correlates of HAdV GI infection in this setting have remained poorly recognized, especially among adult HSCT recipients. DESIGN OR METHODS: We retrospectively studied the prevalence and risk factors of HAdV GI-tissue infection in HSCT recipients (73 adults and 15 children) with GI symptoms who underwent GI-tissue biopsy between January-2012 and December-2017. The presence of HAdV in the GI tissues was determined by real-time PCR. RESULTS: HAdV GI-tissue infection was detected in 21 (23.9%) patients, with similar infection rates identified in adults and children. GI-tissue detection was more common at late (>100 days) compared to early times post-transplantation (50% vs. 12.9%, p < .001). The presence of bloody diarrhea, Arab ethnicity (p = .014) and concurrent cytomegalovirus GI-tissue detection (p = .025) were significantly correlated with HAdV GI-tissue infection, while chronic graft versus host disease was of borderline association (p = .055). CONCLUSIONS: Our findings reveal a high rate and new clinical-demographic correlates of HAdV GI-tissue infection in adult and pediatric HSCT recipients with GI symptoms. The findings highlight the need for future prospective studies to assess the relatedness of HAdV infection to the GI symptoms, and the prevalence, impact, and treatment of HAdV GI infection in HSCT recipients.

Metagenomic sequencing for investigation of a national keratoconjunctivitis outbreak, Israel, 2022.

BackgroundEpidemics of keratoconjunctivitis may involve various aetiological agents. Microsporidia are an uncommon difficult-to-diagnose cause of such outbreaks.AimDuring the third quarter of 2022, a keratoconjunctivitis outbreak was reported across Israel, related to common water exposure to the Sea of Galilee. We report a comprehensive diagnostic approach that identified Vittaforma corneae as the aetiology, serving as proof of concept for using real-time metagenomics for outbreak investigation.MethodsCorneal scraping samples from a clinical case were subjected to standard microbiological testing. Samples were tested by calcofluor white staining and metagenomic short-read sequencing. We analysed the metagenome for taxonomical assignment and isolation of metagenome-assembled genome (MAG). Targets for a novel PCR were identified, and the assay was applied to clinical and environmental samples and confirmed by long-read metagenomic sequencing.ResultsFluorescent microscopy was suggestive of microsporidiosis. The most abundant species (96.5%) on metagenomics analysis was V. corneae. Annotation of the MAG confirmed the species assignment. A unique PCR target in the microsporidian rRNA gene was identified and validated against the clinical sample. The assay and metagenomic sequencing confirmed V. corneae in an environmental sludge sample collected at the exposure site.ConclusionsThe real-time utilisation of metagenomics allowed species detection and development of diagnostic tools, which aided in outbreak source tracking and can be applied for future cases. Metagenomics allows a fully culture-independent investigation and is an important modality for public health microbiology.

Real-Life Comparison of Fosfomycin to Nitrofurantoin for the Treatment of Uncomplicated Lower Urinary Tract Infection in Women.

In this study, we compared the failure rates of fosfomycin and nitrofurantoin for uncomplicated urinary tract infections. We used Meuhedet Health Services' large database to collect data on all female patients, older than 18 years, who were prescribed either antibiotic during 2013-2018. Treatment failure was a composite endpoint of hospitalization, emergency-room visit, IV antibiotic treatment, or prescription of a different antibiotic, within seven days of the initial prescription. Reinfection was considered when one of these endpoints appeared 8-30 days following the initial prescription. We found 33,759 eligible patients. Treatment failure was more common in the fosfomycin group than the nitrofurantoin group (8.16% vs. 6.87%, p-value < 0.0001). However, reinfection rates were higher among patients who received nitrofurantoin (9.21% vs. 7.76%, p-value < 0.001). Among patients younger than 40 years, patients treated with nitrofurantoin had more reinfections (8.68% vs. 7.47%, p value = 0.024). Treatment failure rates were mildly higher in patients treated with fosfomycin, despite having less reinfections. We suggest that this effect is related to a shorter duration of treatment (one vs. five days) and encourage clinicians to be more patient before declaring fosfomycin failure and prescribing another antibiotic.

Characteristics of endovascular pneumococcal infections; a decade of nationwide surveillance study.

In order to characterize pneumococcal endovascular infection in the post-vaccination era, a retrospective nationwide study based on the Israeli Adult IPD database was conducted. Between 2010 and 2019, 0.6% (23 cases) of IPD cases were of endovascular type, occurring mainly in males (72.3%) with underlying medical conditions (78.2%). Additional pneumococcal source (10 patients) and concomitant infections were not uncommon. Penicillin and ceftriaxone susceptibility rates were 65.2% and 91.3%, respectively; 60.9% of the isolates were not covered by the pneumococcal conjugate vaccine. 21.7% of patients died during hospitalization. In conclusion, pneumococcal endovascular infections still carry significant morbidity and mortality.

Bacteremia with Carbapenemase-Producing Enterobacterales in Immunocompromised Patients Colonized with These Bacteria.

We aimed to analyze rates and risk factors for carbapenemase-producing Enterobacterales (CPE) bloodstream infection (BSI) in CPE-colonized patients with malignancies or following hematopoietic cell transplantation. We retrospectively collected data on demography, underlying disease, colonizing CPE, treatment, intensive care unit (ICU) hospitalization, CPE-BSI, and mortality in CPE-colonized immunocompromised patients (2014-2020). Two hundred twenty-one patients were colonized with 272 CPE: 254 (93.4%) carried one carbapenemase [KPC (50.4%), NDM (34.6%), OXA-48-like (5.2%), and VIM (3.3%)]; 18 (6.6%) carried two carbapenemases. Twenty-eight (12.7%) patients developed CPE-BSI. Univariate analysis revealed CPE-BSI-associated factors: younger age, carbapenem or aminoglycoside exposure, ICU admission, neutropenia, carrying serine carbapenemase-producing, and specifically KPC-producing bacteria, colonization with several CPE, and detection of several carbapenemases. None of 23 auto-HSCT recipients developed CPE-BSI. In multivariate analysis, ICU hospitalization was significantly associated with CPE-BSI (odds ratio [OR] 2.82, 95% CI 1.10-7.20; p = 0.042); solid tumor diagnosis was protective (OR 0.21, 95% CI 0.05-1.01; p = 0.038). One-year crude mortality was 108/221 (48.8%), including 19/28 (67.9%) and 89/193 (46.1%) in patients with and without CPE-BSI, p = 0.104. To conclude, CPE-BSI is rare in CPE-colonized patients with solid tumors and following auto-HSCT. ICU hospitalization increased CPE-BSI risk. These data can help to guide empirical anti-CPE antibiotic therapy in patients colonized with these bacteria.

Nurses' and Physicians' Responses to a New Active Antimicrobial Stewardship Program: A Two-Phase Study of Responses and Their Underlying Perceptions and Values.

BACKGROUND: Successful implementation of an antimicrobial stewardship program (ASP) depends on staff members' response to it. We introduced at the Hadassah Medical Center in Israel a significant change to our long-standing handshake ASP. As before, the new ASP involved a dialogue between the treating physician and the infectious disease physician over the appropriate antibiotic therapy. The main change was that the infectious disease physician's decision was now integrated into the patient's electronic medical record (EMR). Our purpose in this study was to uncover the concerns and expectations of physicians and nurses towards the new ASP, before and after its implementation, and link these with their basic perceptions of the ASP and their personal values. METHODS: We used open-ended questions and Likert-type scales to study staff members' personal values, basic perceptions of the new system, and attitudes towards it, both before (N = 143), and one year after (N = 103) the system's implementation. Relationships of the system's perceptions and personal values with attitudes toward the system were tested using correlations and multiple regression analyses. RESULTS: Prior to its implementation, physicians and nurses had multiple concerns about the new ASP's demandingness and inefficiency and its threat to physicians' autonomy and expertise. They also had positive expectations for benefits to the hospital, the patients and society. A year later, following the system's implementation, concerns dissipated, whereas the perceived benefits remained. Moreover, staff members' attitudes tended to be more positive among those who value conformity. CONCLUSION: Introducing new ASPs is a challenging process. Our findings suggest that hospital staff's initial concerns about the new ASP were primarily about its ease of use and demandingness. These concerns, which diminished over time, were linked with perceived satisfaction with the system. Conformity values had an indirect effect in predicting satisfaction with the system, mediated by perceptions of the system as straightforward.

Clinical characteristics and outcome of infective endocarditis due to Abiotrophia and Granulicatella compared to Viridans group streptococci.

OBJECTIVE: To describe the clinical characteristics and outcome of Abiotrophia and Granulicatella infective endocarditis and compare them with Viridans group streptococci infective endocarditis. METHODS: All patients in the International Collaboration on Endocarditis (ICE) - prospective cohort study (PCS) and the ICE-PLUS cohort were included (n = 8112). Data from patients with definitive or possible IE due to Abiotrophia species, Granulicatella species and Viridans group streptococci was analyzed. A propensity score (PS) analysis comparing the ABI/GRA-IE and VGS-IE groups according to a 1:2 ratio was performed. RESULTS: Forty-eight (0.64%) cases of ABI/GRA-IE and 1,292 (17.2%) VGS-IE were included in the analysis. The median age of patients with ABI/GRA-IE was lower than VGS-IE (48.1 years vs. 57.9 years; p = 0.001). Clinical features and the rate of in-hospital surgery was similar between ABI/GRA-IE and VGS-IE (52.1% vs. 45.4%; p = 0.366). Unadjusted in-hospital death was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 8.8%; p = 0.003), and cumulative six-month mortality was lower in ABI/GRA-IE than VGS-IE (2.1% vs. 11.9%; p<0.001). After PS analysis, in-hospital mortality was similar in both groups, but six-month mortality was lower in the ABI/GRA IE group (2.1% vs. 10.4%; p = 0.029). CONCLUSIONS: Patients with ABI/GRA-IE were younger, had similar clinical features and rates of surgery and better prognosis than VGS-IE.

Prevalence of Antibiotic Tolerance and Risk for Reinfection Among Escherichia coli Bloodstream Isolates: A Prospective Cohort Study.

BACKGROUND: Tolerance is the ability of bacteria to survive transient exposure to high concentrations of a bactericidal antibiotic without a change in the minimal inhibitory concentration, thereby limiting the efficacy of antimicrobials. The study sought to determine the prevalence of tolerance in a prospective cohort of E. coli bloodstream infection and to explore the association of tolerance with reinfection risk. METHODS: Tolerance, determined by the Tolerance Disk Test (TDtest), was tested in a prospective cohort of consecutive patient-unique E. coli bloodstream isolates and a collection of strains from patients who had recurrent blood cultures with E. coli (cohorts 1 and 2, respectively). Selected isolates were further analyzed using time-dependent killing and typed using whole-genome sequencing. Covariate data were retrieved from electronic medical records. The association between tolerance and reinfection was assessed by the Cox proportional-hazards regression and a Poisson regression models. RESULTS: In cohort 1, 8/94 isolates (8.5%) were tolerant. Using multivariate analysis, it was determined that the risk for reinfection in the patients with tolerant index bacteremia was significantly higher than for patients with a nontolerant strain, hazard ratio, 3.98 (95% confidence interval, 1.32-12.01). The prevalence of tolerance among cohort 2 was higher than in cohort 1, 6/21(28.6%) vs 8/94 (8.5%), respectively (P = .02). CONCLUSIONS: Tolerant E. coli are frequently encountered among bloodstream isolates and are associated with an increased risk of reinfection. The TDtest appears to be a practicable approach for tolerance detection and could improve future patient management.

Bacteremia in Children with Solid Tumors: Etiology, Antimicrobial Susceptibility, Factors Associated with Multidrug Resistance, and Mortality.

This retrospective study aims to describe the etiology and resistance patterns of pathogens causing bacteremia in children with solid tumors in a tertiary pediatric hematology-oncology center in Jerusalem, Israel (2011-2019). Factors associated with multidrug-resistant (MDR) bacteremia and mortality were analyzed. A total of 228 pathogens were isolated in 126 patients; 61.0% were gram-negative rods (GNR) and 38.2% were gram-positive cocci (GPC). The most common pathogens were Klebsiella pneumoniae (19.3%), Escherichia coli (17.5%), and coagulase-negative staphylococci (16.2%). The proportion of MDR-GNR was 18.2%, while the proportion of MDR-GPC was 55.2%. In logistic regression analysis, breakthrough bacteremia on a penicillin-group antibiotic (odds ratio [OR] 5.69, [95% confidence interval 1.42-22.76], p-value = 0.014) was associated and underlying diagnosis of neuroblastoma was inversely associated (OR 0.17, [0.04-0.81], p-value = 0.026) with MDR-GNR bacteremia; while the previous hospitalizations' duration (OR 1.032/day, [1.01-1.06], p-value = 0.007) and oncologic treatment intensity (OR 2.19, [1.08-4.45, p-value = 0.03) were associated with MDR-GPC bacteremia. Shock, prolonged profound neutropenia, and pediatric intensive care unit (PICU) admission were associated with 7-day mortality; and relapsed disease, oncologic treatment intensity, prolonged profound neutropenia, and PICU admission-with 30-day mortality in the univariate analyses. Empirical antibiotic choice should be based on factors associated with MDR infections in this specific population.

Neutrophils impose strong immune pressure against PfEMP1 variants implicated in cerebral malaria.

Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the iRBC surface. PfEMP1 expression determines the cytoadhesive properties of the iRBCs and is implicated in severe malaria. To evade antibody-mediated responses, the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently, it became clear that in addition to antibody-mediated responses, PfEMP1 triggers innate immune responses; however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here, we show that neutrophils recognize and kill blood-stage P. falciparum isolates. We identify neutrophil ICAM-1 and specific PfEMP1 implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria.

Socioeconomic variations determine the clinical presentation, aetiology, and outcome of infective endocarditis: a prospective cohort study from the ESC-EORP EURO-ENDO (European Infective Endocarditis) registry.

AIMS: Infective endocarditis (IE) is a life-threatening disease associated with high mortality and morbidity worldwide. We sought to determine how socioeconomic factors might influence its epidemiology, clinical presentation, investigation and management, and outcome, in a large international multicentre registry. METHODS AND RESULTS: The EurObservational Programme (EORP) of the European Society of Cardiology EURO-ENDO (European Infective Endocarditis) registry comprises a prospective cohort of 3113 adult patients admitted for IE in 156 hospitals in 40 countries between January 2016 and March 2018. Patients were separated in three groups, according to World Bank economic stratification [group 1: high income (75.6%); group 2: upper-middle income (15.4%); group 3: lower-middle income (9.1%)]. Group 3 patients were younger [median age (interquartile range, IQR): group 1, 66 (53-75) years; group 2, 57 (41-68) years; group 3, 33 (26-43) years; P < 0.001] with a higher frequency of smokers, intravenous drug use, and human immunodeficiency virus infection (all P < 0.001) and presented later [median (IQR) days since symptom onset: group 1, 12 (3-35); group 2, 19 (6-54); group 3, 31 (12-62); P < 0.001] with a higher likelihood of developing congestive heart failure (13.6%, 11.1%, and 22.6%, respectively; P < 0.001) and persistent fever (9.8%, 14.2%, and 27.9%, respectively; P < 0.001). Among 2157 (69.3%) patients with theoretical indication for cardiac surgery, surgery was performed less frequently in group 3 patients (75.5%, 76.8%, and 51.3%, respectively; P < 0.001), who also demonstrated the highest mortality (15.0%, 23.0%, and 23.7%, respectively; P < 0.001). CONCLUSION: Socioeconomic factors influence the clinical profile of patients presenting with IE across the world. Despite younger age, patients from the poorest countries presented with more frequent complications and higher mortality associated with delayed diagnosis and lower use of surgery.